Cardiovascular Health Across the Life Course

Many Roads to Rome

Sarah Urbut, MD PhD

Massachusetts General Hospital

2025-10-19

The Life Course Paradigm

Current Risk Models: The 10-Year Problem

Traditional Approach:

  • 10-year ASCVD risk (PCE)
  • Treatment at thresholds (≥7.5%)
  • Static, single time point

The Question:

“Who will have an event in the next 10 years?”

What’s Missing:

  • Young patients with high lifetime risk
  • Different disease trajectories
  • Optimal intervention timing
  • Information that accrues over time

Better Question:

“What is their lifetime burden, and when should we intervene?”

Many Roads to Rome

Four Trajectories

Trajectory 1: Early Genetic Risk

Profile:

  • High polygenic risk score (PRS) or FH
  • Elevated LDL from young age
  • CAD by age 45-50

Key Evidence:

  • Ference, NEJM 2012: Lifetime cholesterol lowering >> short-term intensive
  • Khera, Nat Genet 2018: PRS identifies missed high-risk individuals
  • AHA 2022: PRS highly predictive in younger populations

The Concept:

Genetics provides early signal → Lower threshold for intervention

Trajectory 2: Metabolic Pathway

Progression:

  1. Prediabetes (age 40-45)
  2. Type 2 diabetes (age 45-50)
  3. Metabolic syndrome (age 50-55)
  4. CAD (age 55-60)

Key Evidence:

  • DPP: Lifestyle intervention delays diabetes
  • Look AHEAD: Weight loss reduces CV events
  • EMPA-REG, LEADER: GLP-1/SGLT2i benefit

The Concept:

Biomarkers accumulate → Intervene at transition points

Trajectory 3: Inflammatory Pathway

Profile:

  • Rheumatologic disease (RA, psoriasis)
  • Often normal lipids
  • “Low” 10-year PCE risk
  • Chronic systemic inflammation

Key Evidence:

  • CANTOS: IL-1β inhibition reduces CV events
  • Colchicine trials: Anti-inflammatory benefit
  • ACC Statement: Inflammation as CV target

The Concept:

Alternative risk pathway → Missed by traditional models

Trajectory 4: Healthy Ager

Characteristics:

  • Maintained low risk across decades
  • Favorable genetics + lifestyle?
  • Resilience to aging

Questions:

  • What protects this group?
  • Can we replicate their trajectory?
  • Genomics? Lifestyle? Microbiome?

The Concept:

Learn from success → Identify protective factors

The Life Course Approach

Information Accrues Over Time

Starting Point (Age 30-40):

  • Genetics (fixed)
    • Polygenic risk scores
    • Family history
    • Monogenic conditions (FH)

This provides the baseline trajectory

Over Time (Age 40-70):

  • Biomarkers (dynamic)
    • Serial lipids, BP, glucose
    • Inflammatory markers
    • Novel biomarkers
  • Imaging (periodic)
    • CAC scoring
    • Carotid ultrasound
    • CT angiography
  • Events (sentinel)
    • Diabetes diagnosis
    • Hypertension
    • Other comorbidities

Uncertainty decreases as information accumulates

Traditional vs. Life Course

Implementation

Tools for Life Course Assessment

Available Now:

  • LIVE-CVD: Lifelong benefit calculator
  • PRS: Clinical labs offer testing ($50-200)
  • CAC scoring: Widely available imaging
  • SCOT-HEART: CT angiography trials

On the Horizon:

  • AI-enhanced imaging
  • EHR-embedded calculators
  • Continuous monitoring (wearables)
  • Multi-omics integration

Challenges:

  • Clinical:
    • EHR integration
    • Workflow burden
    • Training needed
  • Payer:
    • Coverage for “healthy” patients
    • Long-term value demonstration
    • Reimbursement models
  • Patient:
    • Understanding lifetime risk
    • Motivation for prevention
    • Health literacy

Key Discussion Questions

  1. How do we reconcile population models with individualized prediction?

    • When to override risk thresholds based on trajectory?
  2. Can life-course prediction be practically implemented?

    • What barriers to payer coverage for preventive therapies?
  3. How do we bridge lifetime risk with current practice?

    • Lower thresholds? Earlier age? Public health?
  4. Communication:

    • How to make genetics, AI, imaging meaningful?
  5. Testing strategies:

    • Universal CAC at age 40?
    • Who gets genetic testing? When?

Summary

Key Takeaways

The Core Concept:

  • Multiple trajectories to CVD
  • Genetics provides early signal
  • Information accumulates over time
  • Uncertainty decreases with data

The Opportunity:

  • Earlier intervention for high-risk trajectories
  • Avoid overtreatment of low-risk
  • Precision prevention timing

The Path Forward:

  • Integrate genetics + biomarkers + imaging
  • Build clinical decision support
  • Demonstrate cost-effectiveness
  • Engage stakeholders (payers, clinicians, patients)

The Question:

How do we move from 10-year risk thresholds to lifetime trajectory management?

Thank You

Sarah Urbut, MD PhD

Massachusetts General Hospital

surbut@mgh.harvard.edu

Questions for Discussion:

  1. Which trajectories resonate with your practice?
  2. What’s your biggest barrier to life course prevention?
  3. What would change your practice tomorrow?